rs80359771
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.9580_9581del(p.Pro3194AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T3193T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9580_9581del | p.Pro3194AsnfsTer2 | frameshift_variant | 26/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9580_9581del | p.Pro3194AsnfsTer2 | frameshift_variant | 26/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251424Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135886
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461772Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727206
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 20, 2007 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jun 21, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 28, 2023 | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251424 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 9150154 (1997), 29164420 (2018), 32939053 (2021)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in patients with personal or family history of BRCA2-related cancers (Hkansson 1997, Nilsson 2017); Not observed at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9808_9809del and 9808delCC; This variant is associated with the following publications: (PMID: 10570174, 9150154, 9699678, 11861370, 10615237, 30720243, 33674644, 29446198, 29164420) - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2022 | Variant summary: BRCA2 c.9580_9581delCC (p.Pro3194AsnfsX2) results in a premature termination codon, predicted to cause a truncation in exon 26 of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes. c.9580_9581delCC has been reported in the literature in individuals with a personal and/or family history of breast/ovarian cancer (example Hakansson_1997, Nilsson_2018, Olafsdottir_2020). Truncations of the exon 27 COOH-terminal domain of Brca2 have been found to negatively impact the repair of double-strand DNA breaks in mouse cells and mice with a homozygous germline deletion of Brca2 exon 27 are highly suseptible to developing a wide spectrum of solid tumors, suggesting the variant has an affect protein function (Morimatsu_1998, McAllister_2002). Five clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 19, 2020 | The p.Pro3194AsnfsX2 variant in BRCA2 was reported in the literature in 2 individuals with breast cancer (Hakansson 1997 PubMed: 9150154). This vairant has been identified in 0.0009% (1/113708) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3194 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301404.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change creates a premature translational stop signal (p.Pro3194Asnfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs765456206, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as 9808delCC. ClinVar contains an entry for this variant (Variation ID: 38249). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2023 | The c.9580_9581delCC pathogenic mutation, located in coding exon 25 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 9580 to 9581, causing a translational frameshift with a predicted alternate stop codon (p.P3194Nfs*2). This mutation (designated as 9808delCC) was reported in a Scandinavian breast and ovarian cancer family (Håkansson S et al. Am. J. Hum. Genet., 1997 May;60:1068-78). This mutation was reported in a Swedish breast cancer patient diagnosed at age 70 (Nilsson MP et al. Breast Cancer Res. Treat., 2018 Feb;168:117-126). This mutation has also been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 2 nucleotides in exon 26 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at